4-(cinnolinylamino or quinazolinylamino)benzenesulphonamides and intermediates therefor

ABSTRACT

Novel quinazoline and cinnoline derivatives having the formula ##STR1## (wherein one of A and B is CH and the other one of A and B is N; X 1  is halogen or CF 3  and X 3  is one of the groups II, III, IV or V ##STR2## where Q is lower alkylene; R 1  is hydrogen or lower alkyl; R 2  and R 3  are independently lower alkyl or R 2  and R 3  are a divalent radical such that HNR 2  R 3  is a secondary cyclic amine with 5 to 7 ring atoms; R 4  is lower alkyl; n is 0 or 1; the rings shown in formulae III and IV are piperidine or pyrrolidine optionally substituted by lower alkyl; and the ring shown in formula V is piperazine optionally substituted by lower alkyl) and their pharmaceutically acceptable salts are useful as pharmaceuticals particularly as anti-hypertensives. Novel intermediates are also described including the corresponding sulphonic acids of formula I (where A, B and X 1  are defined above and X 3  is OH).

The invention relates to novel quinazoline and cinnoline derivativesthat are useful as pharmaceuticals, particularly as anti-hypertensiveagents. The invention also provides processes for their preparation,pharmaceutical compositions containing them, novel compounds useful asintermediates for the preparation of the said derivatives and a processfor the preparation of the intermediate compounds.

The invention provides, as novel quinazoline and cinnoline derivatives,compounds having the general formula I ##STR3## wherein one of A and Bis CH whilst the other one of A and B is N; X₁ is halogen ortrifluoromethyl and X₃ represents a group having one of formulae II,III, IV and V ##STR4## wherein Q is lower alkylene; R₁ is hydrogen orlower alkyl; R₂ and R₃ are, independently, lower alkyl or R₂ and R₃together form a divalent radical such that R₂ R₃ NH is a secondarycyclic amine with 5 to 7 ring atoms; R₄ is lower alkyl; n is 0 or 1; thering illustrated in formulae III and IV is a piperidine or pyrrolidinering that may be substituted on one or more carbon ring members by loweralkyl and the ring illustrated in formula V is a piperazine ring thatmay be substituted on one or more carbon ring members by lower alkyl;and the pharmaceutically acceptable salts thereof. These compounds areindicated for pharmaceutical use, particularly as anti-hypertensiveagents.

It will be apparent to those skilled in the art that the abovedefinition of X₃ includes moieties possessing an asymmetric carbon atomespecially for instance in the cases where Q is present and is a chainof 1 to 4 methylene groups, the chain being mono-substituted by methylor ethyl or where X₃ is of formula IVa or IIIa ##STR5##

It is to be understood that formula I is intended to encompass eachenantiomer where the compound contains an asymmetric carbon atom andmixtures of enantiomers, for instance, a racemic mixture of enantiomers.Separation of enantiomers can be carried out using general methods knownin the literature.

When A is CH whilst B is N the compounds of the invention arequinazoline derivatives. Where A is N whilst B is CH the compounds ofthe invention are cinnoline derivatives.

X₁ may substitute any of the 5,6,7 and 8 positions of the quinazoline orcinnoline ring system, but is preferably at the 7- or 8- position,advantageously the 7- position. Where X₁ is at the 7-position, formula Imay be represented as Ia ##STR6## X₁ represents halogen, for instancechlorine or bromine, or trifluoromethyl. X₁ is preferably chlorine.

In formulae II and IV, R₁ represents hydrogen or lower alkyl (forinstance methyl, ethyl, propyl, butyl). R₁ is preferably hydrogen. Informulae II, III and IV Q is lower alkylene which may be a straightchain i.e. a chain of 1 to 6, preferably 1 to 4, methylene groups.Alternatively Q may be a branched lower alkylene group, for instance, achain of 1 to 4 methylene groups, the chain being mono- ordi-substituted by methyl or monosubstituted by ethyl. R₂ and R₃ informulae II and III, when separated, are each lower alkyl (for instance,methyl, ethyl, propyl, butyl). Alternatively R₂ and R₃ may be joinedtogether to form a divalent radical such that R₁ R₂ NH is a secondarycyclic amine with 5 to 7 ring atoms, e.g. pyrrolidine, piperidine,morpholine or thiomorpholine. In this case R₁ and R₂ may together havethe formula --(CH₂)₂ --X₂ --(CH₂)₂ -- where X₂ is --(CH₂)_(n) --, O or Swhere n is 0, 1 or 2. R₂ and R₃ are preferably lower alkyl. n in formulaIII and IV is 0 or 1. R₄ in formulae IV and V is lower alkyl (forinstance, methyl, ethyl, propyl, butyl). The ring attached to --(Q)_(n)-- in formulae III and IV is a piperidine or pyrrolidine ring whosenitrogen atom is shown in the formula. The ring may be substituted onone or two ring carbon atoms by lower alkyl (for instance methyl, ethyl,propyl, butyl). The ring carbon atoms are preferably unsubstituted. Thering attached to R₄ in formula V is a piperazine ring (whose nitrogenatoms are shown in the formula). The piperazine ring may be substitutedon one or two ring carbon atoms by lower alkyl (for instance methyl,ethyl, propyl, butyl), but is preferably unsubstituted.

Advantageously X₃ is a group having the formula IIa or IVa ##STR7##wherein Q is alkylene of 1 to 4 carbon atoms; R₂, R₃ and R₄ are,independently, alkyl of 1 to 4 carbon atoms and m is 0 or 1.

The term "lower" as used herein to refer to such groups as alkyl,alkoxy, alkanoyl and alkylene, indicates that the group contains up to6, preferably up to 4, carbon atoms. The group may be in the form of astraight chain or may be branched.

The compounds having formula I form acid addition salts with acids.Examples of acid addition salts are those formed from inorganic andorganic acids and in particular include the sulphate, hydrochloride,hydrobromide, hydroiodide, nitrate, phosphate, sulphonates (for instancethe methanesulphonate or p-toluenesulphonate), acetate, maleate,fumarate, tartrate, malonate, citrate and formate.

The invention also provides, as novel quinazoline and cinnolinederivatives, compounds having the general formula VI ##STR8## (where X₁,A and B are as defined above and X₄ is --OH or --NR₁ R₅ where R₅ ishydrogen or a group having the formula --Q--Z where Q is as definedabove and Z is a leaving group or atom, preferably a halogen atom or anorganosulphonyloxy group, advantageously chlorine, bromine, C₁ -C₆alkanesulphonyloxy, or substituted or unsubstituted benzenesulphonyloxy,for instance, tosyloxy and R₁ is as defined above) and their salts. Suchsalts include acid addition salts and also sulphonate salts of thesulphonic acid where X₄ is --OH. The compounds having formula VI andtheir salts are useful as intermediates for the preparation of compoundshaving the formula I and their pharmaceutically acceptable acid additionsalts.

A first process according to the invention is for the preparation ofcompounds having the formula ##STR9## (where A, B and X₁ are as definedabove and X₅ represents X₃, --OH or --NHR₁ where X₃ and R₁ are asdefined above) or a salt thereof, wherein a compound having the formulaVIII ##STR10## (wherein X₅ is as defined above) or a salt thereof isreacted with a compound having the formula IX ##STR11## (where X₁, A andB are as defined above and Z is a leaving group or atom, preferably ahalogen atom such as iodine, bromine or chlorine) and, if desired, acompound having formula VII (where X₅ is --OH or --NHR₁) is convertedinto a salt thereof or a compound having formula VII (where X₅ is X₃) isconverted into a pharmaceutically acceptable salt thereof or a salt of acompound having formula VII is converted into the compound havingformula VII.

The reaction of the compounds VIII and IX can be carried out in aqueousalcohol with or without acid catalysis. The compounds of formula IX aregenerally known or, if new, can be prepared in known manner. Thesulphonamides (VIII where X₅ is --NHR₁ or X₃) can be prepared byacetylating the sulphanilic acid, converting the N-(acetyl) sulphanilicacid into its sulphonyl chloride derivative, sulphonylating a compoundof formula R₁ NH₂ or X₃ H or a salt thereof with the sulphonyl chlorideand hydrolysing the sulphonylation product to give the desiredaminobenzenesulphonamide. Alternatively, the preparation can be carriedout by converting 4-nitrobenzenesulphonic acid into its sulphonylchloride derivative, sulphonylating a compound of formula R₁ NH₂ or X₃ Hor a salt thereof with the sulphonyl chloride and reducing the nitrogroup to give the desired aminobenzenesulphonamide.

A further class of novel intermediates according to the invention areuseful for the preparation of compounds having formula I where X₃ hasformula IV where n is 1. These novel intermediates have formula IVb##STR12## and their acid addition salts where Y is --NH₂ (amino),protected amino, for instance lower alkanoylamino, preferably acetamido,or latent amino, preferably nitro and R₁, Q, R₄ and the ring attached toR₄ have the same meanings as in formula IV. The compounds having formulaIVb may be prepared by sulphonylating a compound having the formula IVc##STR13## to introduce a sulphonyl group having the formula ##STR14##where Y₁ is protected amino or latent amino and, where Y is --NH₂,converting the protected amino or latent amino group Y₁ of thesulphonation product into amino, for instance, by reduction of nitro orhydrolysis of lower alkanoylamino.

The compounds obtained by the aforesaid process where R₅ is hydroxy andtheir salts can be used to prepare the sulphonamide intermediates andend products by forming a sulphonylating agent, preferably the sulphonylchloride, and sulphonylating ammonia or an appropriate amine or a saltthereof. Accordingly a second process provided by this invention is forthe preparation of compounds having the formula X ##STR15## (where X₁, Aand B are as defined above and X₆ is X₃ (as defined above) or --NR₁ R₅where R₁ and R₅ are as defined above) and the salts thereof. Accordingto this process a compound of general formula X₆ H (XI) where X₆ is asdefined above or a salt thereof is sulphonylated to introduce thesulphonyl group of general formula XII ##STR16## (where X₁, A and B areas defined above) and, if desired, a compound having formula X isconverted into a salt thereof or a salt of a compound having formula Xis converted into the compound having formula X.

As sulphonylating agent, the sulphonyl chloride is preferably used. Thereaction can be carried out in known manner for sulphonylation ofammonia and amines. The sulphonylation can be carried out in a suitablesolvent, for instance, chloroform or methylene chloride, in the presenceof a base to neutralise the hydrogen chloride formed. The base may beprovided by using, for instance, an alkali metal carbonate orbicarbonate or a tertiary amine, for instance, triethylamine or anexcess of the basic compound having formula X₆ H.

The chemical intermediate sulphonamides of the invention (formula VIwhere X₄ is --NR₁ R₅) may be prepared as described above with referenceto formula VII where X₅ is --NHR₁ or formula X where X₆ is --NR₁ R₅. Inthe case where X₄ is --NHR₁ the sulphonamide may be converted into someof the end product sulphonamides by alkylation under basic conditions.Accordingly a third process provided by the invention is for thepreparation of a compound having the general formula XIII ##STR17##(wherein X₁, A, B and R₁ are as defined above and X₇ represents a grouphaving the formula XIV or XV ##STR18## (wherein Q, n, R₂, R₃, R₄ and thering shown in formula XV have the same meanings as defined underformulae II and IV) or a pharmaceutically acceptable salt thereof,wherein a compound having the formula XVI ##STR19## (where X₁, X₂, A, Band R are as defined above) is reacted with a compound having theformula Z--X₇ (XVII) (where Z and X₇ are as defined above) under basicconditions and, if desired, the resultant compound of formula XIII isconverted into a pharmaceutically acceptable salt thereof.

The above process may be carried out in known manner for the alkylationof sulphonamides. The product XIII may be recovered as such or as anacid addition salt by known isolation procedures.

The intermediate sulphonamides of formula VI where X₄ is --NH₂ and thesulphonamides of formula XIII (where R₁ is hydrogen) may also bealkylated to introduce R₁ as lower alkyl. Accordingly the invention alsoprovides a process for the preparation of a compound having the formulaXVIII ##STR20## (where X₁, A and B are as defined above; R₁ * is loweralkyl and X₈ is X₇ or hydrogen) or a salt thereof, wherein a compoundhaving the formula XIX ##STR21## (wherein X₁, X₈, A and B are as definedabove) is reacted with an alkylating agent under basic conditions tointroduce the lower alkyl group R₁ * and, if desired, the resultantcompound having formula XVIII is converted into a salt thereof. Thisprocess may be carried out in accordance with known procedures foralkylation of sulphonamides. The product (XIX) may be recovered as suchor as an acid addition salt by known isolation procedures.

It will be apparent that the sulphonamides of formula I where X₃ is offormula II or IV in which R₁ is lower alkyl and their pharmaceuticallyacceptable salts can be prepared from corresponding sulphonamides whosesulphonamide nitrogen atom is unsubstituted by applying the third andfourth processes of the invention in either order. Either one of X₇ andthe lower alkyl group represented by R₁ is introduced as a first stepand the other one of X₇ and the lower alkyl group is introduced as asecond step.

The intermediate sulphonamides having formula VI where X₄ is --NR₁--Q--Z can also be used to prepare some of the end compounds of theinvention. Accordingly the invention also provides a process for thepreparation of a compound having the formula ##STR22## (wherein X₁, Aand B are as defined under formula I and R₁, R₂, R₃ and Q are as definedunder formula II) or a pharmaceutically acceptable salt thereof, whereina compound having the formula wherein X₁, A, B, Q and R₁ are as definedabove under formula XX, and Z is as explained under formula VI) isreacted with a compound having the formula HNR₂ R₃ (XXII) in which R₂and R₃ are as defined under formula XX or a salt thereof and, ifdesired, a compound having formula XX is converted into apharmaceutically acceptable salt thereof or a salt of a compound havingformula XX is converted into a compound having formula XX. The reactionof the compound XXI with the amine XXII can be carried out inconventional manner for the conversion of secondary amines into tertiaryamines, preferably under pressure.

The novel compounds having general formula I and their pharmaceuticallyacceptable salts are indicated for use as anti-hypertensive agents. Thecompounds may be tested for their response on the blood pressure ofspontaneously hypertensive rats in the following procedure:

The blood pressure of male or female conscious rats that arespontaneously hypertensive are measured in a 39° C. constant temperaturehousing by means of a tail cuff. Rats with systolic pressures below 155mm Hg are not used. Groups of rats (4 per group) are dosed orally withthe test substance in a suitable vehicle or with vehicle alone. Systolicpressures are recorded before dosing and at selected time pointsafterwards (2 hours, 6 hours and 24 hours).

The following table indicates results obtained in the proceduredescribed above:

    ______________________________________                                                             Blood pressure                                                                (as % of blood pressure                                  Compound  Dose       before dosing)                                           (identified by                                                                          (millimoles                                                                              After    After  After                                    Example No.)                                                                            per Kg)    2 hours  6 hours                                                                              24 hours                                 ______________________________________                                        3         0.03       80       67     102                                                0.03       77       70     85                                                  0.015     84       75     86                                                  0.003     92       85     91                                       5         0.03       83       75     95                                       6         0.03       77       67     97                                       7         0.03       71       73     98                                       8         0.03       98       85     107                                      9         0.03       71       62     70                                       16b       0.03       74       58     85                                       ______________________________________                                    

The invention also provides a pharmaceutical composition comprising acompound having formula I or a pharmaceutically acceptable acid additionsalt thereof in association with a pharmaceutically acceptable carrier.Any suitable carrier known in the art can be used to prepare thepharmaceutical composition. In such a composition, the carrier isgenerally a solid or liquid or a mixture of a solid and a liquid.

Solid form compositions include powders, granules, tablets, capsules(e.g. hard and soft gelatin capsules), suppositories and pessaries. Asolid carrier can be, for example, one or more substances which may alsoact as flavouring agents, lubricants, solubilisers, suspending agents,fillers, glidants, compression aides, binders or tablet-disintegratingagents; it can also be an encapsulating material. In powders the carrieris a finely divided solid which is in admixture with the finely dividedactive ingredient. In tablets the active ingredient is mixed with acarrier having the necessary compression properties in suitableproportions and compacted in the shape and size desired. The powders andtablets preferably contain up to 99%, e.g. from 0.03 to 99%, preferably1 to 80% of the active ingredient. Suitable solid carriers include, forexample, calcium phosphate, magnesium stearate, talc, sugars, lactose,dextrin, starch, gelatin, cellulose, methyl cellulose, sodiumcarboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ionexchange resins.

The term "composition" is intended to include the formulation of anactive ingredient with encapsulating material as carrier to give acapsule in which the active ingredient (with or without other carriers)is surrounded by the carrier, which is thus in association with it.Similarly cachets are included.

Liquid form compositions include, for example, solutions, suspensions,emulsions, syrups, elixirs and pressurised compositions. The activeingredient, for example, can be dissolved or suspended in apharmaceutically acceptable liquid carrier such as water, an organicsolvent, a mixture of both or pharmaceutically acceptable oils or fats.The liquid carrier can contain other suitable pharmaceutical additivessuch as solubilizers, emulsifiers, buffers, preservatives, sweeteners,flavouring agents, suspending agents, thickening agents, colours,viscosity regulators, stabilisers or osmo-regulators. Suitable examplesof liquid carriers for oral and parenteral administration include water(particularly containing additives as above e.g. cellulose derivatives,preferably sodium carboxymethyl cellulose solution), alcohols (includingmonohydric alcohols and polyhydric alcohols e.g. glycerol and glycols)and their derivatives and oils (e.g. fractionated coconut oil andarachis oil). For parenteral administration the carrier can also be anoily ester such as ethyl oleate and isopropyl myristate. Sterile liquidcarriers are used in sterile liquid form compositions for parenteraladministration.

Liquid pharmaceutical compositions which are sterile solutions orsuspensions can be utilized by, for example, intramuscular,intraperitoneal or subcutaneous injection. Sterile solutions can also beadministered intravenously. When the compound is orally active it can beadministered orally either in liquid or solid composition form.

Preferably the pharmaceutical composition is in unit dosage form, e.g.as tablets or capsules. In such form, the composition is sub-divided inunit dose containing appropriate quantities of the active ingredient;the unit dosage forms can be packaged compositions, for example packetedpowders, vials, ampoules, prefilled syringes or sachets containingliquids. The unit dosage form can be, for example, a capsule or tabletitself, or it can be the appropriate number of any such compositions inpackage form. The quantity of the active ingredient in unit dose ofcomposition may be varied or adjusted from 0.5 mg or less to 750 mg ormore, according to the particular need and the activity of the activeingredient. The invention also includes the compounds in the absence ofthe carrier where the compounds are in unit dosage form.

The invention is illustrated by the following examples:

EXAMPLE 1 4-(7-Chloro-4-quinazolinylamino)benzenesulphonic acid

Sulphanilic acid (12.1 g, 0.07 mole) was partly dissolved in 280milliliters of aqueous ethanol (50% by volume) at reflux and4,7-dichloroquinazoline (13.9 g, 0.07 mole) was added rapidly in a fewportions. The mixture was refluxed for a further 15 minutes, cooled andfiltered to give the title compound hemihydrate of melting point greaterthan 300° C.

Analysis: Calculated for C₁₄ H₁₀ ClN₃ O₃ S.1/2H₂ O: C, 48.8%; H, 3.22%;N, 12.2%. Found: C, 48.7%; H, 3.32%; N, 11.8%.

The sulphonyl chloride hydrochloride derivative of the title compoundmay be prepared by the following procedure. The title compound (12.6 g,0.036 mole) was heated to reflux for 4 hours in thionyl chloride (90 ml)containing dimethylformamide (0.75 ml). Excess thionyl chloride wasevaporated under reduced pressure and the solid was washed with tolueneto give the sulphonyl chloride hydrochloride (13.9 g).

EXAMPLE 2 4-(7-Chloro-4-cinnolinylamino)benzenesulphonic acid

Sulphanilic acid (1.95 g) in water (75 ml) and ethanol (10 ml) at 70° C.was treated with 4,7-dichlorocinnoline (2.2 g) and ethanol (10 ml) wasadded. The resultant green suspension was stirred vigorously overnightat 70° C. The mixture was cooled, and the solid was filtered, washedwith water and dried at room temperature to give 3.45 g of the titlecompound as the monohydrate, melting point greater than 280° C.

Analysis: Calculated for C₁₄ H₁₀ ClN₃ O₃ S.H₂ O: C,47.53%; H, 3.42%; N,11.88%. Found: C, 47.4%; H, 3.36; N, 11.71%.

The sulphonyl chloride hydrochloride derivative of the title compound isprepared from the title compound in a similar manner to that used inExample 1, last paragraph.

EXAMPLE 3 4-(7-Chloro-4-quinazolinylamino)-N-(2-diethylaminoethyl)benzenesulphonamide

4-(7-Chloro-4-quinazolinylamino)benzenesulphonyl chloride hydrochloride(36.0 g obtainable from the title compound of Example 1) and methylenechloride (180 ml) were cooled under nitrogen to 5° C.N,N-Diethylethylenediamine (35.4 g) was then added at 5°-10° C. over 20minutes to give a light yellow solution. The solution was stirred for 2hours under nitrogen at 5° to 15° C. and then water (200 ml) was added.A white solid precipitated. The mixture was cooled to 10° C. and thesolid was filtered off, washed with water (2×40 ml) and with chloroform(2×40 ml) and dried in an oven to give 279 g of title compound.

A 27 g sample of the title compound was recrystallised and convertedinto the hydrochloride by the following procedure. The sample wasdissolved in refluxing acetone (350 ml). The mixture was filtered hotand solvent was distilled off to give a volume of 100 ml of mixture. Themixture was cooled to about 10° C. and then filtered. The white solidwas collected, washed with acetone (2×50 ml) and dried in an oven togive 23.5 g of title compound.

The recrystallised title compound was suspended in isopropyl alcohol(100 ml) and water (50 ml). Concentrated hydrochloric acid was addeduntil the pH of the mixture was 1. The mixture was stirred for 20minutes and filtered and the collected solid was washed with water (2×15ml), isopropyl alcohol (2×30 ml) and dried in an oven overnight to yield18.5 g of the title compound hydrochloride.

A sample of the title compound was converted into its hydrochloride bydissolving in warm ethanol and adding ethereal hydrogen chloride to givethe title compound as its hydrochloride, three quarters ethanolate, m.p.203° C.

Analysis: Found: C, 51.5%; H, 5.86%; N, 13.5%. C₂₀ H₂₄ ClN₅ O₂S.HCl.3/4C₂ H₆ O requires C, 51.1%; H, 5.88%; N, 13.9%.

EXAMPLE 41-[4-(7-Chloro-4-quinazolinylamino)benzenesulphonyl]-4-methylpiperazine

N-Methylpiperazine (1.0 g, 0.01 mole) was dissolved in chloroform (50ml). Sodium carbonate (10 g) was dissolved in water (50 ml). Thesolutions were combined and cooled to 10° C.4-(7-Chloro-4-quinazolinylamino)benzenesulphonyl chloride hydrochloride(3.85 g, 0.01 mole) was added in portions to the vigorously stirredsolution. Stirring was continued for one hour. The chloroform layer wasseparated, dried and evaporated. The resulting gummy solid wasredissolved in chloroform and chromatographed on an alumina column.Elution with chloroform gave a first band which was discarded. Thesecond band was obtained as a low melting solid, which was converted tothe hydrochloride by dissolving in ethanol and adding ethereal hydrogenchloride to give the title compound as the sesquihydrochloride (650 mg)m.p. 237°-239° C.

Analysis: Found: C, 48.3%; H, 4.58%; N, 14.8%. C₁₉ H₂₀ ClN₄ O₂ S.3/2HClrequires C, 48.7%; H, 4.80%; N, 14.7%.

EXAMPLE 5 4-(7-Chloro-4-quinazolinylamino)-N-(1-ethyl-3-piperidyl)benzenesulphonamide

3-Amino-1-ethylpiperidine (1.1 g, 0.0087 mole) was dissolved inchloroform (50 ml), sodium carbonate (10 g) was dissolved in water (50ml) and the combined solutions were cooled to 10° C.4-(7-Chloro-4-quinazolinylamino) benzenesulphonyl chloride hydrochloride(3.4 g, 0.0087 mole) was added in portions to the vigorously stirredsolutions. Stirring was continued for one hour. The chloroform layer wasseparated, dried and evaporated to give a gummy solid which wastriturated twice with benzene to give a colourless solid (1.1 g). Thiswas found to contain benzene. The solid was therefore chromatographedthrough an alumina column and eluted with chloroform to give a solidwhich was converted to the hydrochloride by dissolving in ethyl acetateand adding ethereal hydrogen chloride to give the title compound as itsdihydrochloride (700 mg). No definite m.p. was exhibited but thecompound softens above 175° C.

The infra-red spectrum of the title compound exhibits prominent peaks at2672, 1614, 1561, 1439, 1376, 1156, 1096, 880, 702 and 600 cm⁻¹.

Analysis: Found: C, 48.2% H, 5.04%; N, 13.1%. C₂₁ H₂₄ ClN₅ O₂S.2HCl.1/4H₂₀ requires C, 48.2%; H, 5.10%; N, 13.4%.

EXAMPLE 6 4-[7-Chloro-4-cinnolinylamino]-N-(2-diethylaminoethyl)benzenesulphonamide

A mixture of anhydrous sodium carbonate (3.08 g) andN,N-diethylethylenediamine (0.43 ml) in chloroform (30 ml) wasvigorously stirred at 5° C. and treated with4-(7-Chloro-4-cinnolinylamino)benzenesulphonyl chloride hydrochloride(1.0 g). The mixture was stirred at room temperature for 11/2 hours andthen filtered. The filtrate was evaporated to give a residue thatcrystallised from ethanol to give the title compound (0.456 g), m.p.175°-76° C.

Analysis: Found: C, 55.3%; H, 5.6%; N, 16.0%. C₂₀ H₂₄ ClN₅ O₂ S requiresC, 55.36%; H, 5.57%; N, 16.14%.

EXAMPLE 7 4-[7-Chloro-4-cinnolinylamino]-N-(1-ethyl-3-piperidyl)benzenesulphonamide

3-Amino-1-ethylpiperidine (0.4 ml) in chloroform (15 ml) was treatedwith anhydrous sodium carbonate (2.94 g) in water (15 ml) and cooled to3° C. The mixture was vigorously stirred and treated with4-(7-chloro-4-cinnolinylamino)benzenesulphonylchloride hydrochloride(1.0 g). The dark orange mixture was stirred at 3° C. for 15 minutes,then at room temperature for 45 minutes. During this period the colourlightened considerably. The chloroform layer was separated and driedover magnesium sulphate. The residue on evaporation solidified whentriturated with methanol, to give the title compound (0.5 g), m.p.213°-15° C. (with decomposition).

Analysis: Found: C, 56.4; H, 5.6; N, 15.65%. C₂₁ H₂₄ ClN₅ O₂ S requiresC, 56.56; H, 5.42; N, 15.7%.

EXAMPLE 8 4-(7-Chloro-4-quinazolinylamino)-N-[2-(1-pyrrolidinyl)ethyl]benzenesulphonamide

4-(7-Chloro-4-quinazolinylamino)benzene sulphonyl chloride,hydrochloride (3.5 g, 0.011 mole) was added portionwise to awell-stirred mixture of sodium carbonate (11.5 g) in water (120 ml) andN-(2-aminoethyl)-pyrrolidine (1.26 g, 0.01 mole) in chloroform (120 ml)at about 10° C. After 1 hour at room temperature, the mixture wasfiltered. The chloroform layer was separated, dried (MgSO₄) andevaporated under reduced pressure to give a gum. Trituration from ethylacetate gave a white solid (1.14 g) which could be crystallised fromethanol-water, m.p. 203°-204.5° C.

Analysis: Found: C, 56.0%; H, 5.40%; N, 16.1%. C₂₀ H₂₂ ClN₅ O₂ Srequires: C, 55.6%; H, 5.13%; N, 16.2%.

EXAMPLE 9 4-(7-Chloro-4-quinazolinylamino)-N-[(2-(1-ethyl)pyrrolidinyl)methyl]benzenesulphonamide

4-(7-Chloro-4-quinazolinylamino)benzenesulphonyl chloride hydrochloride(13.0 g, 0.033 mole) was added portionwise to a well stirred mixture ofsodium carbonate (33 g) in water (350 ml) and2-(aminomethyl)-1-ethylpyrrolidine (4.3 g, 0.033 mole) in chloroform(350 ml), at 10° C. After 1 hour at room temperature, the mixture wasfiltered and the solid washed with water, then dried (vacuum oven).Recrystallisation from ethanol gave the title compound (6.74 g), m.p.199°-201° C.

Analysis: Found: C, 56.3%; H, 5.43%; N, 15.6%. C₂₁ H₂₄ ClN₅ O₂ Srequires: C, 56.6%; H, 5.42%; N, 15.7%.

EXAMPLE 10N-(3-Chloropropyl)-4-(7-chloro-4-quinazolinylamino)-Benzenesulphonamide

4-(7-Chloro-4-quinazolinylamino)benzenesulphonyl chloride hydrochloride(11.7 g, 0.03 mole) was added portionwise to a well stirred mixture ofsodium carbonate (45 g) in water (350 ml) and 3-chloropropylaminehydrochloride (3.9 g, 0.03 mole) in chloroform (350 ml) was added at 10°C. After about 1 hour at room temperature, the mixture was filtered andthe solid was washed with water and then dried to give 7.4 g of thetitle compound. A sample was recrystallised from a mixture of ethanoland water to give the title compound, m.p. 168°-171° C.

Analysis: Found: C, 50.0%; H, 4.07%; N, 13.5%. C₁₇ H₁₆ Cl₂ N₄ O₂ Srequires C, 49.6%; H, 3.92%; N, 13.6%.

EXAMPLE 11 4-(7-Chloro-4-quinazolinylamino)-N-(3-diethylaminopropyl)benzenesulphonamide

A solution of the title compound of Example 10 (4.1 g, 0.01 mole) inethanol (120 ml) containing diethylamine (20 ml, 0.2 mole) was heated to120° in a bomb for 5 hours and then left at room temperature overnight.Evaporation of the solvent under reduced pressure gave a crude redsolid, which was chromatographed with alumina (basic) and 1%ethanol/chloroform. Recrystallisation from ethanol-water gave a whitesolid (1.43 g). A second recrystallisation of a 1.0 g sample fromethanol/water gave the title compound as the hemihydrate (0.84 g),melting point 163°-165° C.

Analysis: Found: C, 54.9%; H, 5.61%; N, 15.3%. C₂₁ H₂₆ ClN₅ O₂ S.1/2H₂ Orequires C, 55.2%; H, 5.96%; N, 15.3%.

EXAMPLE 12 4-(7-Chloro-4-quinazolinylamino)-N-(2-diethylaminoethyl)benzenesulphonamide (a)N-(2-Chloroethyl)-4-(7-Chloro-4-quinazolinylamino) benzenesulphonamide

This compound is prepared in a similar manner to Example 10 using2-chloroethylamine hydrochloride (0.03 moles) instead of3-chloropropylamine hydrochloride.

(b) 4-(7-Chloro-4-quinazolinylamino)-N-(2-diethylaminoethyl)benzenesulphonamide

This compound can be prepared in a similar manner to Example 11 usingthe title compound of part (a) [0.01 mole] instead of the title compoundof Example 10 and a bomb temperature of 100° C. instead of 120° C.

EXAMPLE 13 4-(7-Chloro-4-cinnolinylamino)-N-(2-diethylaminoethyl)benzenesulphonamide (a) 4-(7-Chloro-4-cinnolinylamino)-N-(2-chloroethyl)benzenesulphonamide

This compound is prepared in a similar manner to the procedure ofExample 10 using equimolar quantities of 2-chloroethylaminehydrochloride instead of 3-chloropropylamine hydrochloride and4-(7-chloro-4-cinnolinylamino)benzenesulphonyl chloride hydrochlorideinstead of 4-(7-chloro-4-quinolinylamino) benzenesulphonyl chloride.

(b) 4-(7-Chloro-4-cinnolinylamino)-N-(2-diethylaminoethyl)benzenesulphonamide

This compound is prepared in a similar manner to Example 11 using thetitle compound of part (a) [0.01 mole] instead of the title compound ofExample 10 and a bomb temperature of 100° C. instead of 120° C.

EXAMPLE 14 (a) 4-(6-Chloro-4-quinazolinylamino)benzenesulphonic acid

4,6-Dichloroquinazoline (5.9 g, 0.03 mole) was added portionwise tosulphanilic acid (5.2 g, 0.03 mole) in 50% aqueous ethanol (200 ml) at90° C. with stirring. The mixture was refluxed for 2 hours, cooled andfiltered. The solid was washed with 50% aqueous ethanol and dried in anoven to give the title compound (9.2 g) as the hemihydrate m.p. greaterthan 300° C.

Analysis: Found: C, 48.6%; H, 3.28%; N, 11.9%. C₁₄ H₁₀ ClN₃ O₃ Srequires C, 48.8%; H, 3.22%; N, 12.2%.

(b)4-(6-Chloro-4-quinazolinylamino)-N-(2-diethylaminoethyl)benzenesulphonamid

The sulphonyl chloride hydrochloride derivative of the sulphonic acid ofpart (a) was used to sulphonylate N,N-diethylethylenediamine using asimilar procedure to Example 8. The crude product obtained afterevaporation of solvent from the chloroform layer was a brown solid whichwas purified by column chromatography (basic alumina: 1%ethanol/chloroform) to give a creamy white solid. Recrystallisation fromethanol/water gave the title compound hemihydrate, m.p. 110°-113° C.

Analysis: Calculated for C₂₀ H₂₄ ClN_(S) O₂ S.1/2H₂ O C, 54.2%; H,5.69%; N, 15.8%. Found C, 54.3%; H, 5.64%; N, 16.1%.

EXAMPLE 15 (a)4-Acetylamino-N-[(1-ethyl-2-pyrrolidinyl)methyl]benzenesulphonamide

4-Acetylaminobenzenesulphonyl chloride (7.3 g, 0.03 mol) was addedportionwise to a well stirred mixture of aqueous sodium carbonate (21.2g. in 250 ml of water) and 2-aminomethyl-1-ethylpyrrolidine (4.0 g. 0.03mol) in chloroform (250 ml) at about 10°. The ice bath used for coolingwas removed. After 2 hours the chloroform layer was separated, dried(MgSO₄) and then evaporated under reduced pressure to give a gum, whichslowly crystallised (11.6 g). Recrystallisation from cold ethanol,followed by recrystallisation from water gave the pure title compoundm.p. 94°-96° C..

Analysis Found: C, 52.5%; H, 7.39%; N, 12.0%. C₁₅ H₂₃ N₃ O₃ S.H₂ Orequires C, 52.5%; H, 7.34%; N, 12.2%. (b)4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]benzenesulphonamide

4-Acetylamino-N-[(1-ethyl-2-pyrrolidinyl)methyl]benzenesulphonamide (6.5g, 0.02 mol) was dissolved in 50 ml of 2N aqueous sodium hydroxide. Thesolution was heated to reflux, with stirring, for 11/2 hours. Thesolution was cooled and the pH was adjusted to about 8 with hydrochloricacid (2N). The mixture was extracted with chloroform (3×50 ml) and thecombined extracts were dried (MgSO₄) and evaporated under reducedpressure to give a solid (4.9 g). The solid was purified by columnchromatography (basic Al₂ O₃ : 1% ethanol/chloroform), followed byrecrystallisation from water, to give the pure title compound m.p.109°-110° C.

Analysis Found: C, 55.2%; H, 7.59%; N, 15.1%. C₁₃ H₂₁ N₃ O₂ S requiresC, 55.1%; H, 7.47%; N, 14.8%.

EXAMPLE 16 (a) 4-(7-Trifluoromethyl-4-quinazolinylamino)benzenesulphonicacid

0.8 grams of sulphanilic acid and an equimolar quantity of4-chloro-7-trifluoromethylquinazoline were heated in 20 ml of 50%aqueous ethanol at 100° C. for 2 hours. The suspension was cooled andthe solid was filtered off, washed with water and dried to give 1.03 gof the title compound. The sulphonyl chloride hydrochloride derivativefor use in part (b) below was prepared in similar manner to Examples 1and 2.

(b)N-[(1-ethyl-2-pyrrolidinyl)methyl]-4-(7-trifluoromethyl-4-quinazolinylamino)benzamide

A mixture of 2-aminomethyl-1-ethylpyrrolidine (0.34 ml; 0.00235 mole),anhydrous sodium carbonate (3.5 g) and chloroform (100 ml) was cooled onan ice bath and treated with 4-(7-trifluoromethyl-4-quinazolinylamino)benzene sulphonylchloride hydrochloride (1.0 g; 0.00235 mole) withvigorous sitrring. The mixture was stirred at ambient temperature for 4hours and then filtered. The residue on evaporation of the solvent wastriturated with ether and the resulting solid was filtered off, washedwith a little ether and dried to give the quarter hydrate of the titlecompound (0.28 g), melting point 150°-152° C.

Analysis Found: C, 54.4%; H, 5.0%; N, 14.8%; C₂₂ H₂₄ F₃ N₅ O₂ S.1/4H₂ Orequires C, 54.59%; H, 5.1%; N, 14.47%.

We claim:
 1. A compound selected from those having the formula I##STR23## and their pharmaceutically acceptable salts, wherein one of Aand B is CH whilst the other one of A and B is N; X₁ is selected fromhalogen and trifluoromethyl and X₃ is a group having one of the formulaeII, III, IV ##STR24## wherein Q is lower alkylene; R₁ is hydrogen orlower alkyl; R₂ and R₃, when separate, are independently lower alkyl andR₂ and R₃, when linked together, represent a divalent radical such thatHNR₂ R₃ is a secondary cyclic amine with 5 to 7 ring atoms; R₄ is loweralkyl; n is selected from 0 and 1; the ring illustrated in formulae IIIand IV is selected from the group consisting of piperidine, pyrrolidine,piperidine substituted on at least one ring carbon atom by lower alkyland pyrrolidine substituted on at least one ring carbon atom by loweralkyl and the ring illustrated in formula V is selected from piperazineand piperazine substituted on at least one ring carbon atom by loweralkyl.
 2. A compound as claimed in claim 1, wherein X₁ is at the7-position of the quinazoline or cinnoline ring system.
 3. A compound asclaimed in claim 1, wherein X₃ is a group having one of the formulae IIaand IVa ##STR25## wherein Q is alkylene of 1 to 4 carbon atoms; R₂, R₃and R₄ are independently alkyl of 1 to 4 carbon atoms and m is selectedfrom 0 and
 1. 4. A compound as claimed in claim 1, which is4-(7-Chloro-4-quinazolinylamino)-N-(2-diethylaminoethyl)-benzenesulphonamideor a pharmaceutically acceptable salt thereof.
 5. A compound as claimedin claim 1, which is4-(7-Chloro-4-cinnolinylamino)-N-(2-diethylaminoethyl)-benzenesulphonamideor a pharmaceutically acceptable salt thereof.
 6. A compound as claimedin claim 1, which is4-(6-Chloro-4-quinazolinylamino)-N-(2-diethylaminoethyl)-benzenesulphonamideor a pharmaceutically acceptable salt thereof.
 7. A compound as claimedin claim 1, which is4-[7-Chloro-4-quinazolinylamino]-N-(1-ethyl-3-piperidyl)-benzenesulphonamideor a pharmaceutically acceptable salt thereof.
 8. A compound as claimedin claim 1, which is4-[7-Chloro-4-cinnolinylamino]-N-(1-ethyl-3-piperidyl)-benzenesulphonamideor a pharmaceutically acceptable salt thereof.
 9. A compound as claimedin claim 1, which is1-[4-(7-Chloro-4-quinazolinylamino)benzenesulphonyl]-4-methylpiperazineor a pharmaceutically acceptable salt thereof.
 10. A compound as claimedin claim 1, which is4-(7-Chloro-4-quinazolinylamino)-N-[2-(1-pyrrolidinyl)ethyl]benzenesulphonamide or a pharmaceutically acceptable salt thereof.11. A compound as claimed in claim 1, which is4-(7-Chloro-4-quinazolinylamino)-N-[(2-(1-ethyl)-pyrrolidinyl)methyl]benzenesulphonamideor a pharmaceutically acceptable salt thereof.
 12. A compound as claimedin claim 1, which is4-(7-Chloro-4-quinazolinylamino)-N-(3-diethylaminopropyl)-benzenesulphonamideor a pharmaceutically acceptable salt thereof.
 13. A compound as claimedin claim 1, which isN-[2-diethylaminoethyl]-4-[7-trifluoromethyl-4-quinazolinylamino]benzenesulphonamideor a pharmaceutically acceptable salt thereof.
 14. A pharmaceuticalcomposition comprising an anti-hypertensively effective amount of acompound as claimed in claim 1 in association or combination with apharmaceutically acceptable carrier.